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研究生:楊毅奇
研究生(外文):I-Chi Yang
論文名稱:以PI3K/Akt訊息傳遞路徑抑制劑做為口腔癌治療藥物潛力之研究
論文名稱(外文):Study on the Potential Usage of Phosphatidylinositol 3-kinase/ Akt Pathway Inhibitor for the Treatment of Oral Cancer
指導教授:郭彥彬郭彥彬引用關係
指導教授(外文):Mark Yen-Ping Kuo
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:口腔生物科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:89
中文關鍵詞:口腔癌
外文關鍵詞:PI3KAkt
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根據衛生署民國九十二年癌症登記報告指出,口腔癌在臺灣男性十大癌症中死亡率與發生率皆位居第四位。儘管近年在診斷及治療之科技上有不少進步,但傳統的外科手術、放射線療法和藥物化學療法都不甚令人滿意,整體來說,口腔癌病人之五年存活率並未有明顯改變 。因此,需要一個更好的治療方法來改善整體存活率及生活品質。本實驗室先前發現 phospho-akt(p-Akt) 過度表現與臺灣口腔癌有密切關係。 口腔癌致癌物- 檳榔鹼arecoline和尼古丁也都可以增加p-Akt的活性。 因此本研究擬發展以降低p-Akt 表現為標的口腔癌治療方法。 我們首先利用含有 PTEN 抑癌基因的缺陷腺病毒載體, 感染人類口腔癌細胞株SAS, 結果發現,口腔癌細胞對於缺陷腺病毒載體的感染率約為 23% ,只有控制組 HeLa 細胞的四分之一。 而感染含有 PTEN 抑癌基因的缺陷腺病毒,並無法造成口腔癌細胞凋亡。 我們另外利用LY294002抑制SAS細胞中PI 3-K的活性, 發現高濃度 (40�嵱) 的 LY294002 才能抑制SAS細胞的生長。 在這個濃度 LY294002 對正常口腔黏膜細胞已經有明顯的毒性,因此以基因治療或是藥物直接抑制PI3-K 的活性可能不是未來口腔癌治療的良好策略。
近年研究指出,食用魚藤酮 (rotenone) 的小鼠可減少因口腔致癌物處理而引起癌瘤形成的機率。 而其衍生物-魚藤素(Deguelin) 可藉由 PI3-K依賴及非依賴兩種路徑來抑制肺癌細胞的 p-Akt 活性 。 因此我們進一步探討魚藤酮對人類口腔癌細胞株SAS所造成的影響。我們發現,魚藤酮可以抑制口腔癌細胞的 p-Akt 活性。 同時 ,魚藤酮對於人類口腔癌細胞株具有劑量依賴性 (dose-dependent) 的毒殺效應,會降低SAS的細胞生長與存活。藉由流式細胞儀分析細胞的DNA含量,魚藤酮會造成SAS停滯在G2/M期。而Hoechst 33258染色、TUNEL標定、DNA片段,cytochrome C 的釋放,及PARP和 caspase 3的活化等,更證實魚藤酮引起人類口腔癌鱗狀細胞癌細胞死亡的方式為細胞凋亡。故魚藤酮具有做為口腔癌抗癌藥物的潛力。
另外,在SAS細胞株中,魚藤酮的處理會促使p53蛋白在細胞核中表現以及p53的下游基因如Bax也會隨這時間而增加。但是如p21CIP1/WAF1並沒有隨著魚藤酮處理的時間有增加的趨勢。 不同於過去的研究,我們發現魚藤酮可以同時活化caspase 8 和 caspase 9 ,在 SAS 細胞的培養液中加入 caspase 8和 caspase 9的抑制劑 (Z-LEHD-FMK; Z-IETD-FMK), 皆能減低魚藤酮引起的細胞凋亡,且有加成效果 , 詳細作用機轉有待更進一步研究。
Oral cancer is the fourth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. Continued investigation of new chemotherapeutic agents is thus needed. Recent studies have shown that feeding rotenone inhibited carcinogen-induced mouse oral carcinogenesis. However, the mechanisms by which it inhibits oral carcinogenesis are not well understood.
We examined the effects of rotenone on proliferation, cell cycle and apoptosis of oral cancer cell lines SAS using MTT assay, flow cytometry analysis, TUNEL assay, DNA fragmentation assay and Western blotting of cleaved PARP. Rotenone significantly inhibited the proliferation of SAS oral cancer cell lines in a dose-dependent manner with a 50% inhibition concentration (IC50) of rotenone about 2.35 �嵱. However, the IC50 of normal oral mucosa fibroblasts (OMF) was 44.55�嵱. It was almost 22 times higher than the IC50 of SAS. DNA flow cytometric analysis showed that rotenone treatment induced a G2/M arrest. Rotenone treatment also caused significant apoptosis of SAS cells as evidenced by Hoechst 33258 staining, TUNEL labeling, DNA fragmentation and cleavage of PARP. These results indicate that the inhibitory effects of rotenone on oral carcinogenesis may be related to the G2/M phase arrest and induction of apoptosis. Furthermore, nuclear p53 protein and its downstream targets, p21CIP1/WAF1 and Bax, could be induced in SAS (p53-wild type) cells after treatment with rotenone. Rotenone could induce the activation of caspase 8 and caspase 9 in SAS cells, which was different from the previous studies found in other cell types.
Chapter I 5
INTRODUCTION 5
Oral squamous cell carcinoma 5
The Phosphatidylinositol 3-Kinase/AKT Pathway in human cancer 7
Dysregulation of PI3K-Akt pathway in human cancer 10
Adenovirus for gene therapy of oral cancer 13
Rotenone 15
Apoptosis 19
Regulation of apoptosis 20
Caspases 22
Bcl-2 gene family 24
TNF receptor family 26
P53-dependent apoptosis 28
Research objectives 30

Chapter II 32

MATERIALS AND METHODS 32
Cell and cell culture 32
Immunohistochemical analysis 32
Amplification, purification and titration of the adenovirus 33
Drug treatment 36
Cell viability (MTT) assay 36
Measurement of apoptosis by flow cytometry 37
Hoechst staining 38
TdT-mediated dUTP Nick End Labeling (TUNEL) 38
DNA ladder analysis 39
Western blot analysis 39
Caspase inhibition 41
Cell death detection ELISA 42

Chapter III 43

RESULTS 43
Phospho-AKT expression in oral squamous cell carcinoma 43
Adenovirus-mediated gene transfer to human oral SCC cell line 43
Cell growth inhibition caused by rotenone 44
Cell cycle analysis 44
Induction of apoptosis by rotenone treatment 45
Effect of rotenone on PI3K/Akt signaling pathways in SAS cell line 46
Rotenone induces cytochrome c release and caspase activation 46
Rotenone increases the expression of p53 and bax protein 47

Chapter IV 65
DISSCUSION 65
FUTURE RESEARCHES AND PERSPECTIVES 74
Chapter V 76
REFERENCES 76
REFERENCES
Armstrong JS, Hornung B, Lecane P, Jones DP, Knox SJ. (2001). Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW. Biochem Biophys Res Commun. 289, 973-8.

Bacus, S. S., Gudkov, A. V., Lowe, M., Lyass, L., Yung, Y., Komarov, A. P., Keyomarsi, K., Yarden, Y., and Seger, R. (2001). Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20, 147–155.

Balint EE, Vousden KH. (2001). Activation and activities of the p53 tumour suppressor protein. Br J Cancer 85, 1813-23.

Barker SJ, Reddy EP. (1998). Modulation of life and death by the TNF receptor superfamily. Oncogene 17, 3261-70.

Barnes, D.M. and Gillett, C.E. (1998). Cyclin D1 in breast cancer. Breast Cancer Res. Treat. 52, 1-15.

Barrientos, A., and Moraes, C. T. (1999). Titrating the effects of mitochondrial complex I impairment in the cell physiology. J. Biol. Chem. 274, 16188–16197.

Bates S, Vousden KH. (1999). Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci. 55, 28-37.

Bellacosa, A., Testa, J.R., Staal, S.P., and Tsichlis, P.N. (1991). A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254, 274-277.

Bergelson JM, Cunningham JA, Droguett G, et al.(1997). Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 275, 1320–1323.

Bergelson JM, Krithivas A, Celi L, et al. (1998). The murine CAR homolog is a receptor for coxsackie B viruses and adenoviruses. J Virol. 72, 415–419.

Beutler B, Van Huffel C. (1994). Unraveling function of the TNF ligand and receptor families. Science 264, 667-9.

Bortner CD, Cidlowski JA. (2002). Cellular mechanisms for the repression of apoptosis. Annu Rev Pharmacol Toxicol 42, 259-81.

Brinkley, B. R., Barham, S. S., Barranco, S. C., and Fuller, G. M. (1974). Rotenone inhibition of spindle microtubule assembly in mammalian cells. Exp. Cell Res. 85, 41–46.

Briskin KB, Fady C, Wang M, Lichtenstein A. (1996). Apoptotic inhibition of head and neck squamous cell carcinoma cells by TNF . Arch Otolaryngol Head Neck Surg. 122, 559-63.

Burgering, B.M. and Medema, R.H. (2003). Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J. Leukoc. Biol. 73, 689-701.

Cantley, L.C. and Neel, B.G. (1999). New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. USA 96, 4240-4245.

Chen Z, Seimiya H, Naito M, et al. (1999). ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 18, 173-80.

Chen CH. (1987). An epidemiological study of oral squamous cell carcinoma in southern Taiwan. J Formosan Dent Assoc 10: 268–274.

Cheng EH-Y, Levine B, Boise LH, Thompson CG, Hardwick JM. (1996). Bax-independent inhibition of apoptosis by Bcl-xL. Nature 379, 554-6.

Chong KM. (1966). Betel nut chewing and mouth cancer in Taiwan. Observation of the oral mucosa in the betel nut chewers. J Formosan Med Assoc 65: 79–85.

Chun KH, Kosmeder JW 2nd, Sun S, Pezzuto JM, Lotan R, Hong WK, Lee HY. (2003). Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst. 95, 291-302.

Clayman GL, el -Naggar AK, Lippman SM, et al. (1998). Adenovirusmediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol. 16, 2221–2232.

Clayman GL, el -Naggar AK, Roth JA, et al. (1995). In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res. 55, 1–6.

Clayman GL, Lippman SM, Laramore GE, Hong WK. 1996 Head and neck cancer. (In:) Cancer Medicine (Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum R (eds) pp) 1645–1709 Philadelphia: Williams and Wilkins.

Cunningham,M.L., Soliman,M.S., Badr,M.Z. and Matthews,H.B. (1995). Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver. Cancer Lett., 95, 93–97.

Daftary DK, Murti PR, Bhonsle RR, Gupta PC, Mehta FS, Pindborg JJ. 1991 Risk factors and risk markers for oral cancers in high risk areas of the world. (In:) Oral Cancer: Detection of Patients and Lesions at Risk (Johnson NW (ed) pp) 29–63 Cambridge: Cambridge University Press.

Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: a play in three Akts. Genes Dev. 13, 2905-2927.

Diehl, J.A., Cheng, M., Roussel, M.F., and Sherr, C.J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499-3511.

Ervin TJ, Clark JR, Weichselbaum RR, et al. (1987). An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous- cell carcinoma of the head and neck. J Clin Oncol. 5, 10–20.

Ferry S., Nori-aki M., Hiroshi T., Tetsuro I., Takashi K., Masamichi O., Masato H. (2002). TNF inhibited the apoptosis by activation of Akt serine/threonine kinase in the human head and neck squamous cell carcinoma. Cellular Signaling., 14, 771–778.

Fingar, D.C., Salama, S., Tsou, C., Harlow, E., and Blenis, J. (2002). Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472-1487.

Franceschi S, Talamini R, Barra S. (1990). Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy. Cancer Res 50: 6502–6507.

Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A., and Sessa, W.C. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597-601.

Ganly I, Eckhardt SG, Rodriguez GI, et al. (2000). A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res. 6, 798–806.

Garami, A., Zwartkruis, F.J., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S.C., Hafen, E., Bos, J.L., and Thomas, G. (2003). Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457-1466.

Goebel EA, Davidson BL, Zabner J, et al. (1996). Adenovirusmediated gene therapy for head and neck squamous cell carcinomas. Ann Otol Rhinol Laryngol. 105, 562–567.

Gomez, M., Sampson, J., and Whittemore, V. (1999). The Tuberous Sclerosis Complex. (Oxford, England: Oxford University Press).

Grosss A, McDonell JM, Korsmeyer SJ. (1999). Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899-911.

Gruss H-J, Dower SK. (1995). Tumor necrosis factor ligand superfamily. Involvement in the pathology of malignant melanomas. Blood 85, 3378-404.

Grütter MG.. (2000). Caspases: key players in programmed cell death. Curr Opin Struct Biol. 10, 649-55.

Guo M, Hay BA. (1999). Cell proliferation and apoptosis. Curr Opin Cell Biol. 11, 745-52.

Gupta A. K., Bakanauskas V. J., Cerniglia G. J., Cheng Y., Bernhard E. J., Muschel R. J., McKenna W. G.. (2001). The Ras radiation resistance pathway. Cancer Res., 61, 4278-4282.

Häcker G.. (2000). The morphology of apoptosis. Cell Tissue Res. 301, 5-17.

Hansen,W.H., Davis,K.J. and Fitzhugh,O.G. (1965). Chronic toxicity of cube. Toxicol. Appl. Pharmacol., 7, 535–542.

Horvitz HR. (1999).Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 59, 1701s-6s.

Hsieh LL, Wang PF, Chen IH, Liao CT, Wang HM, Chen MC, Chang JTC, Cheng AJ. (2001). Characteristics of mutations in the p53 genes in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. Carcinogenesis 22: 1497–1503.

Itoh M, Chiba H, Noutomi T, Takada E, Mizuguchi J. (2000). Cleavage of Bax-alpha and Bcl-x (L) during carboplatin-mediated apoptosis in squamous cell carcinoma cell line. Oral Oncol. 36, 277-85.

Itoh N, Yonehara S, Ishii A, et al. (1991). The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233-43.

Jeng JH, Wang YJ, Chiang BL, Lee PH, Chan CP, Ho YS, Wang TM, Lee JJ, Hahn LJ, Chang MC. (2003). Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis. 24, 1301-15.

Johnson NW. 1991 A global view of the epidemiology of oral cancer. (In:) Oral Cancer: Detection of Patients and Lesions at Risk (Johnson NW (ed) pp) 3–26 Cambridge: Cambridge University Press.

Kasono K, Blackwell JL, Douglas JT, et al. (1999). Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector. Clin Cancer Res. 5, 2571–2579.

Kerr JFR, Winterford CM, Harmon BV. (1994). Apoptosis, its significance in cancer and cancer therapy. Cancer 73, 2013-26.

Kerr JFR, Wyllie AH, Currie AR. (1972). Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer. 26, 239-56.

Kerr JFR. (1971). Shrinkage necrosis: a distinct mode of cellular death. J Pathol. 105, 13-29.

Kirn D, Hermiston T, McCormick F. (1998). ONYX-015: clinical data are encouraging. Nat Med. 4,1341–1342.

Klaassen CD, editor. (2001). Casarett and Doull''s toxicology: the basic science of poisons. 6th ed. New York (NY): McGraw-Hill. p. 609–790.

Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. (1995). Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med 24, 450–453.

Kovar, J., Valenta, T., and Stybrova, H. (2001). Differing sensitivity of tumor cells to apoptosis induced by iron deprivation in vitro. In Vitro Cell Dev. Biol. Anim. 37, 450–458.

Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B. (1995). The biochemistry of programmed cell death. FASEB J, 9, 1277-87.

Kuo MYP, Chang HH, Hahn LJ, Wang JT, Chiang CP. (1995). Elevated ras p21 expression in oral premalignant lesions and squamous cell carcinomas in Taiwan. J Oral Pathol Med. 24, 255-60.

Kuo MYP, Jeng JH, Chiang CP, Hahn LJ. (1994). Mutation of ki-ras oncogene codon 12 in betel quid chewing-related human oral squamous cell carcinomas in Taiwan. J Oral Pathol Med. 23, 70-4.

Kurose, K., Gilley, K., Matsumoto, S., Watson, P.H., Zhou, X.P., and Eng, C. (2002). Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat. Genet. 32, 355-357.

Kwon B, Youn BS, Kwon BS. (1999). Functions of newly identified members of the tumor necrosis factor receptor/ligand superfamilies in lymphocytes. Curr Opin Immunol. 11, 340-5.

Larson DL, Lindberg RD, Lane E, et al. (1983). Major complications of radiotherapy in cancer of the oral cavity and oropharynx. A 10 year retrospective study. Am J Surg. 146, 531–536.

Li D, Duan L, Freimuth P, et al. (1999). Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer. Clin Cancer Res. 5, 4175–4181.

Li H, Zhu H, Xu CJ, Yuan J. (1998). Cleavage of BID by caspase-8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501.

Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 278, 8516-25.

Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S.I., Puc, J., Miliaresis, C., Rodgers, L., and McCombie, R. et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947.

Ling YH, Liebes L, Zou Y, Perez-Soler R. (2003). Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem. 278, 33714-23.

Liu TJ, el -Naggar AK, McDonnell TJ, et al. (1995). Apoptosis induction mediated by wild - type p53 adenoviral gene transfer in squamous cell carcinoma of the head and neck. Cancer Res. 55, 3117–3122.

Magnusson C, Vaux DL. (1999). Signalling by CD95 and TNF receptors: not life and death. Immunol Cell Biol. 77, 41-6.

Manning, B.D. and Cantley, L.C. (2003). United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans. 31, 573-578.

Marshall, L. E., and Himes, R. H. (1978). Rotenone inhibition of tubulin self-assembly. Biochim. Biophys. Acta 543, 590–594.

Matsumiya T, Imaizumi T, Yoshida H, Kimura H, Satoh K. (2001). Cisplatin inhibits the expression of X-chromosome-linked inhibitor of apoptosis protein in an oral carcinoma cell line. Oral Oncol. 37, 296-300.

Mayo, L.D. and Donner, D.B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl. Acad. Sci. USA 98, 11598-11603.

Miller CR, Buchsbaum DJ, Reynolds PN, et al. (1998). Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor–independent gene transfer. Cancer Res. 58, 5738–5748.

Miyashita T, Harigai M, Hanada M, Reed JC. (1994). Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 54, 3131-5.

Miyashita T, Reed JC. (1995). Tumor suppressor gene p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293-9.

Nakagawa T, Zhu H, Morishima N, et al. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103.

Nakano K, Vousden KH. (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7, 683-94.

Nicholson DW. (1991). Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028-42.

O’Malley BW Jr, Chen SH, Schwartz MR, et al. (1995). Adenovirusmediated gene therapy for human head and neck squamous cell cancer in a nude mouse model. Cancer Res. 55, 1080–1085.

O’Malley BW, Cope KA, Chen SH, et al. (1996). Combination gene therapy for oral cancer in a murine model. Cancer Res. 56, 1737–1741.

Oda E, Ohki R, Murasawa H, et al. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053-8.

Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M., and Donner, D.B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82-85.

Parker SL, Tong T, Bolden S, Wingo PA. (1996). Cancer statistics. CA Cancer J Clin 46: 5–27.

Pelengaris, S., Khan, M., and Evan, G. (2002). c-myc: more than just a matter of life and death. Nat. Rev. Cancer 2, 764-776.

Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W, Keating MJ, Huang P. (2003). Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem. 278, 37832-9.

Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW. (2004). Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene. 232934-49. Review.

Puthalakath H, Villunger A, O''Reilly LA, et al. (2001). Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293, 1829-32.

Rao RV, Hermel E, Castro-Obregon S, et al. (2001). Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem. 276, 33869-74.

Reed JC. (1998). Bcl-2 family proteins. Oncogene 17, 3225-36.

Rocco JW, Li D, Liggett WH Jr, et al. (1998). p16INK4A adenovirus-mediated gene therapy for human head and neck squamous cell cancer. Clin Cancer Res. 4, 1697–1704.

Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. (1994). Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature (Lond.), 370, 527-532.

Romashkova, J.A. and Makarov, S.S. (1999). NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86-90.

Ruggero, D. and Pandolfi, P.P. (2003). Does the ribosome translate cancer? Nat. Rev. Cancer 3, 179-192.

Ryan KM, Phillips AC, Vousden KH. (2001). Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol. 13, 332-7.

Scaffidi C, Fulda S, Srinivasan A, et al. (1998). Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675-87.

Schendel SL, Azimov R, Pawlowski K, Godzik A, Kagan BL, Reed JC. (1999). Ion channel activity of the BH3 only Bcl-2 family member, Bid. J Biol Chem. 274, 21932-6.

Schmitt, C.A. (2003). Senescence, apoptosis and therapy-cutting the lifelines of cancer. Nat. Rev. Cancer 3, 286-295.

Schmitz I, Walczak H, Krammer PH, Peter ME. (1999). Differences between CD95 type I and II cells detected with the CD95 ligand. Cell Death Differ. 6, 821-2.

Schneider P, Tschopp J. (2000). Apoptosis induced by death receptors. Pharm Acta Helv. 74, 281-6.

Sears, R., Nuckolls, F., Haura, E., Taya, Y., Tamai, K., and Nevins, J.R. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501-2514.

Sen S. (1992).Programmed cell death: concept, mechanism and control. Biol Rev Camb Philos Soc. 67, 287-319.

Seta C, Fujita M, Muraki Y, Fukuda J, Kobayashi S, Haneji T. (2000). Fas expression and Fas monoclonal antibody-induced apoptosis in human squamous cell carcinoma cell line, SCC-25. J Oral Pathol Med. 29, 271-8.

Sewell DA, Li D, Duan L, et al. (1997). Optimizing suicide gene therapy for head and neck cancer. Laryngoscope. 107, 1490–1495.

Sherer TB, Kim JH, Betarbet R, Greenamyre JT. (2003). Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol. 179, 9-16.

Sherr, C.J. and Roberts, J.M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501-1512.

Shimizu, S., Eguchi, Y., Kamiike, W., Waguri, S., Uchiyama, Y., Matsuda, H., and Tsujimoto, Y. (1996). Retardation of chemical hypoxia-induced necrotic cell death by Bcl-2 and ICE inhibitors: Possible involvement of common mediators in apoptotic and necrotic signal transductions. Oncogene 12, 2045–2050.

Shiu MN, Chen TH, Chang SH, Hahn LJ. (2000). Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. Br J Cancer. 82, 1871-4.

Speiser DE, Sebzda E, Ohteki T, et al. (1996). Tumour necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo. Eur J Immunol. 26, 3055-60.

Steck, P.A., Pershouse, M.A., Jasser, S.A., Yung, W.K., Lin, H., Ligon, A.H., Langford, L.A., Baumgard, M.L., Hattier, T., and Davis, T. et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356-362.

Sugimoto, Y., Whitman, M., Cantley, L.C., and Erikson, R.L. (1984). Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc. Natl. Acad. Sci. USA 81, 2117-2121.

Tanaka T, Kohno H, Sakata K, Yamada Y, Hirose Y, Sugie S, Mori H. (2002). Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis. 23,1361-7.

Taylor, W. R., and Stark, G. R. (2001) Regulation of the G2/M transition by p53. Oncogene 20, 1803–1815.

Thompson CB. (1995). Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456-62.

Thornberry NA, Lazebnik Y. (1998). Caspases: enemies within. Science 281, 1312-6.

Tomko RP, Xu R, Philipson L. (1997). HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci USA. 94, 3352–3356.

Tong D, Poot M, Hu D, Oda D. (2000). 5-Fluorouracil-induced apoptosis in cultured oral cancer cells. Oral Oncol. 36, 236-41.

Trotman, L.C. and Pandolfi, P.P. (2003). PTEN and p53: Who will get the upper hand?. Cancer Cell 3, 97-99.

Tsujimoto Y, Shimizu S. (2000). Bcl-2 family: life-or-death switch. FEBS Lett.466, 6-10.

Udeani,G.O., Gerhauser,C., Thomas,C.F., Moon,R.C., Kosmeder,J.W., Kinghorn,A.D., Moriarty,R.M. and Pezzuto,J.M. (1997). Cancer chemopreventive activity mediated by deguelin, a naturally occurring rotenoid. Cancer Res., 57, 3424–3428.

Vaux DL, Korsmeyer SJ. (1999). Cell death in development. Cell 96, 245-54.

Vikram B. (1994) Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 110, 564–565.

Vivanco I, Sawyers CL. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2, 489-501.

Vlahos CJ, Matter WF, Hui KY, Brown RF. (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem., 269, 5241–8.

Vokes EE, Weichselbaum RR, Lippman SM, et al. (1993). Head and neck cancer. N Engl J Med. 328, 184–194.

Vousden KH. (2000). p53: death star. Cell 103, 691-4.

Wallach D, Varfolomeev E, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. (1999). Tumour necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol. 17, 331-67.

Wang X. (2001).The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922-33.

Welch, H.C., Coadwell, W.J., Stephens, L.R., and Hawkins, P.T. (2003). Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett. 546, 93-97.

Whitman, M., Kaplan, D.R., Schaffhausen, B., Cantley, L., and Roberts, T.M. (1985). Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239-242.

Wilson KM, Stambrook PJ, Bi WL, et al. (1996). HSV- tk gene therapy in head and neck squamous cell carcinoma. Enhancement by the local and distant bystander effect. Arch Otolaryngol Head Neck Surg. 122, 746–749.

Wyllie AH, Beattie GJ, Hargreaves AD. (1981). Chromatin changes in apoptosis. Histochem J. 13, 681-92.

Wyllie AH. (1995). The genetic regulation of apoptosis. Curr Opin Genet Dev. 5, 97-104.

Xu, W., Liu, L.Z., Loizidou, M., Ahmed, M., and Charles, I.G. (2002). The role of nitric oxide in cancer. Cell Res. 12, 311-320.

Yuki, K., Miyauchi, T., Kakinuma, Y., Murakoshi, N., Suzuki, T., Hayashi, J., Goto, K., and Yamaguchi, I. (2000). Mitochondrial dysfunction increases expression of endothelin-1 and induces apoptosis through caspase-3 activation in rat cardiomyocytes in vitro. J. Cardiovasc. Pharmacol. 36, S205–S208.
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